Process for the preparation of 5-fluoro-1H-pyrazoles

ABSTRACT

A new process for the preparation of 5-fluoro-1H-pyrazoles of the general formula (I) as described herein comprising reacting an olefin with an hydrazine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a §371 National Stage Application ofPCT/EP2014/075491, filed 25 Nov. 2014, which claims priority to EP13194560.2, filed 27 Nov. 2013.

BACKGROUND Field of the Invention

5-fluoro-1H-pyrazoles, in particular5-Fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole, areimportant building blocks for the preparation of crop protectionchemicals, as those described in WO 2010051926.

Description of Related Art

It is known that5-fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole canbe prepared by the treatment of the dimer of hexafluoropropene withwater free N,N-dimethylhydrazine in diethyl ether at −50° C. followed byheating of the intermediate at 120° C., I. L. Knunyants et al. Izv.Akad. Nauk SSSR, (1990) 2583-2589.

However, this two step transformation requires low temperatures for thefirst step and results in the formation of CH₃F during the thermalelimination in the second step, making this process expensive,environmentally unfriendly, and particularly difficult forindustrialization.

Starting from perfluoro-2-methyl-2-penten and phenylhydrazine, in thepresence of triethylamine at −50° C. 1-Phenylpyrazole has been shown tobe obtainable in 90% yield (SU 1456419). Furin et al. J. Fluor. Chem.98(1999) 29 reported that the reaction of perfluoro-2-methyl-2-pentenewith phenylhydrazine in CH₃CN gave a mixture of isomeric pyrazoles 3 and4 in a ratio 4:1.

Although, commercially available at low cost (especially in the form oftheir water solutions) the use of monoalkylhydrazines for theregioselective synthesis of the said pyrazoles is not known from theprior art. The problem to be solved by this invention was to identify asimple and selective process for preparing 5-fluoro-1H-pyrazoles fromavailable fluoroalkenes and mono-substituted hydrazines, which should inparticular be amenable for an industrial scale process. As an additionaladvantage, this process should have a favorable profile with respect tosafety and production of unwanted waste material.

SUMMARY

Surprisingly, 5-fluoro-1H-pyrazoles of the general formula (I)

can be prepared in high purity and in a short and simple process byreacting an olefin of the general formula (a)

with nucleophiles, followed by reaction with hydrazines of formula (b)R¹—NH—NH₂  (b),whereinR¹ is selected from C₁-C₆ alkyl, cycloalkyl, C₅-C₁₀ aryl, preferablyC₁-C₆ alkyl, more preferably methyl;R² is a trihalomethyl moiety with at least one fluorine atom; andR³ is selected from C₁-C₅ haloalkyl, preferably from CF₃, CF₂Cl, C₂F₅,C₃F₇, CF₂CF₂Cl, CFClCF₃, and whereas the nucleophile is not water.

Surprisingly, is has been found that the interaction of fluoroalkenes offormula (a) in a first step with a nucleophile that is not water,preferably selected from the group consisting of alcohols, thioles,amines, and depending on the basicity of the nucleophile optionally witha base, followed by a reaction of the formed intermediates of formula(c) or (d) with hydrazines of formula (b), proceeds regioselectivelywith high specificity for the formation of only one isomeric pyrazole ofthe formula (I) in high yields.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The preferred nucleophiles utilized in the reaction according to theinvention can be classified as follows:

Step 1: Reactions with Alcohols or Thiols, and a Base

Wherein Y can be oxygen or sulfur and the residues R¹, R², R³ have themeanings as defined above.

Some compounds of formula (c′) and (c″) can be prepared according V.Snegirev et al. Izvestiya Akademii Nauk SSR, Seriya Khimicheskaya, N. 1,pp. 106-119, 1986. Preferred compounds of formula (c) are selected from:

I. Reactions with Secondary Amines and Optionally a Base:

whereinR⁴ is independently selected from an C₁₋₁₂ alkyl, C₃-C₈-cycloalkyl,C₆₋₁₂-aryl or C₆₋₁₂-aryl-C₁₋₄-alkyl, preferably C₁₋₄-alkyl andcyclopropyl; or both R⁴ form together with N to which are bonded a fiveor six-membered ring which contains in addition to the N to which bothR⁴ are bonded ring-atoms selected from the group consisting of C, O, Nand S, preferably selected from C and O forming, e.g. a piperidine,pyrolidine or morpholine moiety, preferably a morpholine moiety. Theresidues R¹, R², R³ have the meanings as defined above.

Compounds of formula (d′) and (d″) can be prepared according to V.Snegirev et al, Izestiya Akademii nauk, SSSR, Seriya Khimicheskaya, N11, pp, 2561-2568, 1982. Preferred compounds of formula V are selectedfrom:

Preferably, nucleophiles are selected from Alkyl₄N OH, alcohols (forexample: methanol ethanol, isopropanol, benzylalkohol), methylamine,ethylamine, dimethylamine. The combination of different nucleophiles isalso possible.

For nucleophiles like alcohols or thioles that are not sufficientlybasic in nature, a base is typically added to the reaction in step 1.For amines, preferably, no additional base is added.

The reaction can be performed in the presence of organic and inorganicbases. Preferred organic bases to carry out the reaction are:trimethylamine, triethylamine, tripropylamine, tributylamin,methydiisopropylamin, N-methylmorpholine, pyridine, alkylpyridines,triomethybenzylammonium hydroxide, tetrabutylalammonim hydroxide, Hünigbase. Preferably base is triethylamine.

Preferred inorganic bases to carry out the reaction are: NaHCO₃, K₂CO₃,NaOH, NaHCO₃, KF, LiOH, CsOH, Cs₂CO₃.

The amount of base is in the range of 1 to 7 equivalents, preferablybetween 1.5 to 4 equivalents, more preferably between 1.5 to 3equivalents per one equivalent of the compound of formula (a).

Generally, the reaction time for the performance of step 1 is not ofcritical importance and can inter alia depend on the reaction volume,nature of the base employed, and the reactivity of the alkene of formula(a). Preferably it is within the range of 1 to 5 h, more preferablywithin the range of 1 to 3 h.

According to a further preferred embodiment of the present invention,the amount of nucleophiles used in the reaction is in the range of 1 to5 equivalents, preferably in the range of 1.2 to 3 equivalents, morepreferably between 1 to 3 equivalents per one equivalent of compound offormula (a).

Step 2: Reaction of Compounds of Formula (c′) or (c″) with Hydrazines ofFormula (b)

The cyclisation (step 2) can be performed in different solvents selectedfrom

a) alkanes, like hexanes e.g. cyclohexane or methylcyclohexane;

b) haloalkanes, preferably dichlorometane, dichlorethane;

c) alcohols, preferably methanol, ethanol, or isopropanol;

d) nitriles, preferably acetonitrile, or butyronitrile;

e) amides, preferably dimethylformamide, or dimethylacetamide;

f) ethers like diethylether, methyltert.butylether, dimethoxyethane,diglym,

g) benzene, toluene, dichlorobenzene, chlorobenzene.

Particularly preferred solvents for the cyclisation are dichloromethane,dichloroethane, acetonitrile and butyronitrile, most preferred solventsfor this reaction are dichloromethane, acetonitrile and butyronitrile

According to a further embodiment of the present invention, thecyclization is performed at temperatures ranging from −5° C. to 50° C.,more preferably at temperatures ranging from 0° C. to 30° C., mostpreferably from 0° C. to room temperature.

Generally, the reaction time is not of critical importance and candepend on the reaction volume, preferably it is within the range of 3 to20 h, more preferably within the range of 1 to 5 h.

The ratio of the compound of formula (III) and the compound of formula(c′, c″) or (d′, d″) can vary within a large range, preferably it iswithin 0.9 to 5 equivalents, more preferably between 1 to 2.5equivalents, even more preferably between 1 to 1.5, and most preferably1 equivalent of (b) per one equivalent of the compound of formula (c′,c″) or (d′, d″). A preferred embodiment of the present invention relatesto a process for preparing pyrazoles of formula (Ia),

wherein R¹ is selected from C₁-C₆ alkyl, preferably methyl, and whichcomprises the reaction of perfluoro-2-methyl-2-pentene

with a hydrazine of general formula (b).R₁—NH—NH₂  (b)

A particularly preferred embodiment of the present invention relates toa process for preparing pyrazoles of formula (Ib),

Perfluoro-2-methyl-2-pentene is commercially available (Fa. Daikin) andP&M Invest (Russia) or can be prepared via dimerization ofhexafluoropropene, see U.S. Pat. No. 5,254,774; R. Haszeldiner et al,Journal of the Chemical Society [Section] D: Chemical Communications(1970), (21), 1444-5.

Monoalkylhydrazines and Monoarylhydrazines are commercially available.

Preferably R¹ is selected from alkyl, particularly preferably it ismethyl.

Preferably R² is selected from CF₃, CF₂Cl, particularly preferably it isCF₃.

Preferably R³ is selected from CF₃, C₂F₅, C₃F₇, CF₂CF₂Cl, CFClCF₃,particularly preferably it is, C₂F₅.

Most preferable is the combination of R¹=methyl, R²=CF₃, R³=C₂F₅.

Step 3

In a Step 3, the compound of formula (I), preferably compound (Ia), canbe transformed into its CN analog of formula (6) or (6a), respectively

wherein R¹ is (C₁-C₄)-alkyl, preferably, a compound of formula (6) is acompound of formula (6a):

by reacting compound (I), preferably compound (Ia), with a CN-donor suchas alkaline cyanides (e.g., NaCN, KCN, CsCN, or CuCN).

Typical solvents are acetonitrile, DMF, DMA, N-methylpyrrolidone (NMP),Sulfolan, dimethoxyethane, diglym. Preferred solvents are acetonitrile,DMF or DMA.

Typically, the temperature for this reaction is between 30° C. and 120°C., preferably between 40° C. and 110° C., more preferably above 60° C.such as between 60° C. and 120° C. or between 60° C. and 100° C.

Generally, the reaction time is not of critical importance and candepend on the reaction volume. Preferably, the reaction time is between2 h and 8 h, more preferably between 4 and 8 h.

Step 4

In a Step 4, a compound of formula (6), preferably (6a), can betransformed in its carboxylic acid analog of formula (7), preferablyformula (7a), respectively, according to hydrolysis steps known in theart:

wherein R¹ is C₁-C₄-alkyl, preferably a compound of formula (7) is acompound of formula (7a):

The conversion of a cyano group (—CN) into a carboxylic group (—COOH) isgenerally performed under acidic or basic conditions.

For acidic hydrolysis, preference is given to mineral acids, for exampleH₂SO₄, HCl, HSO₃Cl, HF, HBr, HI, H₃PO₄ or organic acids, for exampleCF₃COOH, p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid. The reaction can be accelerated by theaddition of catalysts, for example FeCl₃, AlCl₃, BF₃, SbCl₃, NaH₂PO₄.The reaction can likewise be performed without addition of acid, only inwater.

Basic hydrolysis is effected in the presence of inorganic bases such asalkali metal hydroxides, for example lithium hydroxide, sodium hydroxideor potassium hydroxide, alkali metal carbonates, for example Na₂CO₃,K₂CO₃ and alkali metal acetates, for example NaOAc, KOAc, LiOAc, andalkali metal alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu oforganic bases such as trialkylamines, alkylpyridines, phosphazenes and1,8-diazabicyclo[5.4.0]undecene (DBU). Preference is given to theinorganic bases, for example NaOH, KOH, Na₂CO₃ or K₂CO₃. To generate theprotonated acidic form of formula (7) or (7a), respectively, a followingstep of acidification should follow.

Typically, suitable inorganic acids for performing the acidificationafter completion of the basic hydrolysis is any acid which is strongerthan the deprotonated form of a compound of formula (7) or (7a),respectively. Preference is given to mineral acids, for example H₂SO₄,HCl, HF, HBr, HI, H₃PO₄ or organic acids, for example CF₃COOH,p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid. Preferred acids for this acidificationsare HCl or H₂SO₄.

The reaction step can be performed in substance or in a solvent.Preference is given to performing the reaction in a solvent. Suitablesolvents are, for example, selected from the group comprising water,alcohols such as methanol, ethanol, isopropanol or butanol, aliphaticand aromatic hydrocarbons, for example n-hexane, benzene or toluene,which may be substituted by fluorine and chlorine atoms, such asmethylene chloride, dichloroethane, chlorobenzene or dichlorobenzene;ethers, for example diethyl ether, diphenyl ether, methyl tert-butylether, isopropyl ethyl ether, dioxane, diglyme, dimethylglycol,dimethoxyethane (DME) or THF; nitriles such as methyl nitrile, butylnitrile or phenyl nitrile; amides we dimethylformamide (DMF) orN-methylpyrrolidone or mixtures of such solvents, particular preferencebeing given to water, acetonitrile, dichloromethane and alcohols(ethanol). Preferably, the reaction is carried out in water. The processstep of the invention is generally performed under standard pressure.Alternatively, however, it is also possible to work under vacuum orunder elevated pressure (for example reaction in an autoclave withaqueous HCl).

The reaction time may, according to the batch size and the temperature,be selected within a range between 1 hour and several hours such asbetween 1 h and 30 h, preferably between 3 h and 20 h.

Preference is given to conversion by means of basic hydrolysis followedby an acidification.

The process step of the invention is performed preferably within atemperature range from 20° C. to 150° C., more preferably attemperatures of 30° C. to 110° C., most preferably at 30° C. to 80° C.

Generally the reaction time may, according to the batch size and thetemperature, be selected within a range between 1 hour and several hourssuch as between 1 h and 30 h, preferably between 3 h and 20 h.

Compounds of Formula (II)

The present invention also refers to a process to produce aninsecticidal compound of formula (II), preferably of formula (II′), morepreferably of formula (IIa), based on the preparation of compounds offormula (I), more preferably of formula (Ib). Compounds of formula (II)are, e.g., known from WO 2010/051926.

wherein

-   R¹ is C₁-C₄-alkyl, preferably methyl; and-   A₁ is C—R²; and-   R² is hydrogen, fluorine, chlorine, bromine, CN, NO₂, optionally    halogenated C₁-C₆-alkyl, optionally halogenated C₁-C₄-alkoxy,    optionally halogenated C₁-C₄-alkylsulphonyl, optionally halogenated    C₁-C₄-alkylsulphinyl or N-cyclopropylaminocarbonyl    (—C(═O)—NH—cyclopropyl); preferably hydrogen, fluorine, chlorine,    bromine, CN, NO₂, methyl, ethyl, fluoromethyl, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy,    1-methylethoxy, fluoromethoxy, difluoromethoxy,    chlorodifluoromethoxy, dichlorofluoromethoxy, trifluoromethoxy,    2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy,    pentafluoroethoxy, methylsulphonyl, methylsulphinyl,    trifluoromethylsulphonyl, trifluoromethylsulphinyl or    N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine,    chlorine, bromine, CN, NO₂, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or    pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine,    most preferably chlorine; and-   A₂ is C—R³ or nitrogen; and-   R³ is hydrogen, methyl, fluorine or chlorine, preferably hydrogen;    and-   Q is hydrogen, cyano, hydroxy, formyl or one of the groupings    C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₉-cycloalkyl,    C₃-C₉-heterocycloalkyl, C₁-C₄-alkoxy, C₄-C₁₅-alkylcycloalkyl,    C₄-C₁₅-cycloalkylalkyl, C₁-C₆-hydroxyalkyl, C₆-aryl-C₁-C₃-alkyl,    C₅-C₆-heteroaryl-C₁-C₃-alkyl, C₁-C₄-aminoalkyl,    aminocarbonyl-C₁-C₄-alkyl or C₁-C₄-alkyl-amino-C₁-C₄-alkyl which are    optionally substituted with one, two, three, four or five,    preferably with one or two, more preferably with one, substituents    independently selected from the group consisting of hydroxy, nitro,    amino, halogen, C₁-C₃-alkoxy, cyano, hydroxycarbonyl,    C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbamoyl,    C₄-C₆-cycloalkylcarbamoyl and optionally independently with one, two    or three substituents selected from the group consisting of halogen,    cyano, nitro, hydroxycarbonyl, C₁-C₂-alkylcarbamoyl, C₁-C₂-alkyl,    halogenated C₁-C₂-alkyl and C₁-C₂-alkoxy substituted phenyl;    preferably Q is C₃-C₆-cycloalkyl, or C₃-C₆-cycloalkyl which is    substituted with at least one substituent selected from the group    consisting of chlorine, fluorine, bromine, iodine, cyano and    hydroxy, or C₆-aryl-C₁-C₃-alkyl; more preferably cyclopropyl,    1-cyano-cyclopropyl or benzyl (—CH₂—C₆H₅);    preferably, a compound of formula (II) is a compound of formula    (II′):

wherein A¹ and A² and Q are as defined for a compound of formula (II),characterized in that the process comprises steps 1 and 2 as describedabove.

In one preferred embodiment, the compound of formula (II) is compound(IIa) defined by the following substituents:

R¹ A₂ A₁ Q CH₃ C—H C—Cl Benzyl

The new and inventive process for preparing a compound of formula (II),preferably (II′), more preferably (IIa), is characterized in that theprocess comprises steps 1 and 2 as described above. In one preferredembodiment, the process is characterized in that it comprises steps 1and 2 as described above. In another preferred embodiment, the processcomprises in addition to steps 1 and 2 as described above optionallyStep 3 and Step 4 as described above and optionally, by the subsequentStep 6 described below. Optionally, compound (8) in Step 6 can beproduced by the reaction indicated in Step 5 which is described below:

wherein R¹ and A₁ and A₂ and Q have the meanings described for compoundsof formula (II). LG is any desired leaving group, e.g. halogen oranhydrate.

Typically, an amine derivative of the formula (8) does not only refer tothe amine but also to its salt form (8)H⁺ W⁻ wherein W is selected from⁻, Cl⁻, Br⁻, J⁻, HSO₄ ⁻, CH₃COO⁻, BF₄ ⁻, CH₃SO₃ ⁻, Toluensulphonic acid,CF₃COO⁻ or CF₃SO₃ ⁻.

wherein W⁻ is selected from ⁻, Cl⁻, Br⁻, J⁻, HSO₄ ⁻, CH₃COO⁻, BF₄ ⁻,CH₃SO₃ ⁻, Toluensulphonic acid, CF₃COO⁻ or CF₃SO₃ ⁻.

Thus, one preferred embodiment refers to the reaction of Step 6 whereinthe compound of formula (8) is present in its salt form (8)H⁺ W⁻,wherein W⁻ is selected from ⁻, Cl⁻, Br⁻, J⁻, HSO₄ ⁻, CH₃COO⁻, BF₄ ⁻,CH₃SO₃ ⁻, Toluensulphonic acid, CF₃COO⁻ or CF₃SO₃ ⁻.

In one more preferred embodiment, a compound of formula (8) is compound(8a) and/or its salt (8a′):

wherein

-   W⁻ (in the case of compound (8a′)) is selected from the group    consisting of F⁻, Cl⁻, Br⁻, J⁻, HSO₄ ⁻, CH₃COO⁻, BF₄ ⁻, CH₃SO₃ ⁻,    Toluensulphonic acid⁻, CF₃COO⁻ or CF₃SO₃ ⁻.    Step 6

In Step 6, compounds according to the invention of the type (II),preferably (II′), more preferably (IIa), can be synthesized by reactingamines of the general structure (8) (or their salts) with intermediate(7′) which is an activated form of carboxylic acid derivative of formula(7), preferably of formula (7a). The reaction can be carried out with orwithout solvents. In this step, a suitable base can likewise be used.

wherein R¹ is hydrogen, optionally halogenated C₁-C₄-alkyl or optionallyhalogenated cyclopropyl, preferably methyl.

An activated form of carboxylic acid derivative of formula 7, preferablyformula (7a), which is indicated in the reaction scheme of Step 6 aboveby having any leaving group LG in the —C(═O)LG group, encompasses a)analogs of formula (7) or (7a), respectively, wherein the OH of the COOHgroup is replaced by a suitable leaving group such as halogen; b)anhydrates of compounds of formula (7) or (7a), respectively; or c)compounds of formula (7) or (7a), respectively in the presence of acoupling reagent which presence activates the compound of formula (7) or(7a), respectively, in the sense of the present invention, such asdicyclohexylcarbodiimide or 1-hydroxybenzotriazole. The skilled personis aware of suitable leaving groups preparation of anhydrates of acarboxylic acid or suitable coupling reagents for acid/amine reactionsand the preparation of such compounds. Preferred leaving groups arecarboxylic acid halides such as carboxylic acid chlorides or fluorides.

Cyclic carboxylic acid halides, as inter alia represented by the generalstructure (7′), can be prepared simply by reacting a heterocycliccarboxylic acid of compound (7) with halogenating reagents such asthionyl chloride, thionyl bromide, phosphoryl chloride, oxalyl chloride,phosphorus trichloride, etc. (Houben-Weyl (1952) vol. VIII, p. 463 ff.).

Amines derivatives of the formula (7) and their salts are known in theart, commercially available or can be prepared in a known manner (see,e.g., WO 2010/051926).

The synthesis of carboxamides represented by the formula (II),preferably (II′), more preferably (IIa), can, however, also be carriedout using coupling reagents such as dicyclohexylcarbodiimide andadditives such as 1-hydroxybenzotriazole (Konig et al. Chem. Ber.(1970), 788-798). It is also possible to use coupling reagents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1,1′-carbonyl-1H-imidazole and similar compounds.

Coupling reagents which are used for carrying out the synthesis processare all those which are suitable for the preparation of an ester oramide bond (cf. e.g. Bodansky et al., Peptide Synthesis, 2nd ed., Wiley& Sons, New York, 1976; Gross, Meienhofer, The Peptide: Analysis,Synthesis, Biology (Academic Press, New York, 1979).

Furthermore, mixed anhydrides can also be used for the synthesis of(II), preferably (II′), more preferably (IIa) (see, e.g., Anderson etal, J. Am. Chem. Soc (1967), 5012-5017). In this process it is possibleto use various chloroformates, such as, for example, isobutylchloroformate, isopropyl chloroformate. Similarly, diethylacetylchloride, trimethylacetyl chloride and the like can be used for this.

In general, Step 6 can be carried out optionally/if appropriate, in thepresence of a suitable diluent/solvent and, optionally/if appropriate,in the presence of suitable basic reaction auxiliary.

The process according to the invention can be performed in the presenceof a diluent/solvent. Useful diluents for this purpose include all inertorganic solvents, preferably aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, hexane, heptane, cyclohexane,methylcyclohexane, benzene, toluene, xylene or decalin; halogenatedhydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane; ethers such as diethyl ether, diisopropyl ether, methylt-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones such asacetone, butanone, methyl isobutyl ketone or cyclohexanone; nitrilessuch as acetonitrile, propionitrile, n- or i-butyronitrile orbenzonitrile; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone orhexamethylphosphoramide, more preferably are used chlorobenzene andtoluene.

Preferred diluents are aliphatic, alicyclic or aromatic hydrocarbons,for example petroleum ether, hexane, heptane, cyclohexane,methylcyclohexane, benzene, toluene, xylene or decalin; and halogenatedhydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane; e.g. toluene or chlorbenzene.

The solvent which may be used is any solvent which does not adverselyaffect the reaction, such as, for example, water. Of suitability arearomatic hydrocarbons such as benzene or toluene; halogenatedhydrocarbons such as dichloromethane, chloroform or tetrachloromethane,open-chain or cyclic ethers such as diethyl ether, dioxane,tetrahydrofuran or 1,2-dimethoxyethane; esters such as ethyl acetate andbutyl acetate; ketones such as, for example, acetone, methyl isobutylketone and cyclohexanone; amides such as dimethylformamide anddimethylacetamide; nitriles such as acetonitrile; and other inertsolvents such as 1,3-dimethyl-2-imidazolidinone; the solvents can beused alone or in combination of two or more.

The base (basic reaction auxiliary) used can be an acid acceptor such asan organic base such as triethylamine, ethyldiisopropylamine,tri-n-butylamine, pyridine and 4-dimethylaminopyridine; furthermore, thefollowing bases can, for example, be used: alkali metal hydroxides, suchas, for example, sodium hydroxide and potassium hydroxide; carbonatessuch as sodium hydrogencarbonate and potassium carbonate; phosphatessuch as dipotassium hydrogenphosphate and disodium phosphate; alkalimetal hydrides, such as sodium hydride; alkali metal alcoholates, suchas sodium methanolate and sodium ethanolate. These bases can be used inratios of from 0.01 to 5.0 mole equivalents based on (8) and (7′).Furthermore, silver(I) cyanide can also be used as base and activator(see, e.g., Journal of Organic Chemistry. 1992, 57, 4394-4400; Journalof Medicina Chemistry 1992, 35, 3905-3918; Journal of Organic Chemistry2003, 68, 1843-1851).

However, in one preferred embodiment of the present invention, Step 6 iscarried out in the absence of an acid acceptor and the leaving group isCl or F, more preferably Cl.

In the context of the invention, “in the absence of an acid acceptor”means in the absence of an acid acceptor other than the amine reactant(8) or, in other words, “in the absence of an additional acid acceptorwherein “additional” means in addition to the amine derivative of theformula (8) (or its salts (8′) which is part of the reaction. An“additional acid acceptor” in the sense of the present invention can bea base in addition to the amine compound according to the invention orcompounds which reduce the strength of a formed acid such as salts, e.g.silvercyanide (AgCN), which are able to transform strong acids which areformed during the reaction (leaving group anion plus hydrogen cation)into insoluble salts and weak acids (e.g. formed HCl (if the leavinggroup is chlorine) reacts with AgCN to insoluble AgCl and weak baseHCN).

Surprisingly, the carboxamides of the formula (II) can be prepared inthe absence of an acid acceptor with good yields in high purity andselectivity. A further advantage of the process according to theinvention is that the workup is simpler, since an acid acceptor is notneeded. This causes fewer or no waste water, an easier purificationprocess without prior isolation by addition of an aliphatic alcohol inthe same reaction vessel, and the process can be run in a higherconcentration. The resulting product has then been obtained with asurprising purity superior to 90% or even close to 100%, and with lessreagent and effort, while prior conditions in presence of an acidacceptor generally leads to a purity close to less than 90% The processaccording to the invention becomes more economically viable.

Thus, one preferred embodiment refers to a reaction for the productionof compounds of formula (IIa)

wherein leaving group LG refers to F, Cl, Br or I, preferably F or Cl,andin the absence of an acid acceptor in addition to compound (8a).

The suitable reaction temperature is in the range from −20° C. up to theboiling point of the particular solvent. In general, the reactiontemperature is between 70° C. to 150° C., preferably between 80° C. to140° C., e.g. 100° C. or around 100° C. such as 80° C. to 130° C. or 80°C. to 120° C.

The reaction time is between 1 min and 96 h depending on the choice ofvolume, reactants, solvents and reaction temperature.

For the process of Step 6, generally between 0.8 and 1.5 mol, preferably0.8 to 1.4 mol, 0.9 to 1.4 mol, equimolar amounts or 1 to 1.2 mol ofamine derivative of the formula (8) or its salt, preferably (8a) or(8a′), are used per mole of the pyrazole-carboxamide derivatives (7′).

One preferred embodiment refers to a reaction of a compound (8a) or itssalt (8a′), respectively, with compound (7′), wherein X is Cl andwherein the ratio of compound (8a) (or its salt (8a′)) and (7′) whereinX is Cl is between 1:1 or 1:1.3, preferably between 1:1 to 1:2 such asbetween 1:1 to 1:1 or even 1:1.

Depending on the choice of volume, reactants, solvents and reactiontemperature, the reaction time can vary between one minute and 96 h.Typically, the reaction time is up to 15 hours, but the reaction canalso be terminated even earlier in the case of complete conversion.Preference is given to reaction times of 5-10 hours.

The reaction of Step 6 is generally performed under standard pressure.However, it is possible to work under elevated or reducedpressure—generally between 0.1 bar and 10 bar It is preferable to workunder reduced pressure to remove HCl from the reaction volume.

The reaction of Step 6 can generally be performed under atmosphere.However, it is preferred to carry out the process under protective gassuch as argon. or nitrogen.

Moreover the skilled person will understand that it is also possible toreact a compound of formula (7′) with a compound of formula (8*),wherein the —C(═O)—NH-Q moiety of compounds of formula (8) is replacedby a C(═O)—OH or C(═O)-PG moiety in a compound of formula (8*), whereinPG stands for any protective group of a carboxylic group (e.g. amethylesther, i.e. PG represents —O-methyl). The deprotection of thecarboxylic moiety of the resulting compound (II*) of a reaction with acompound (8*) and/or activating of the carboxylic moiety and/couplingwith an amine to arrive at a compound of formula (II) are well known toa skilled person. Compounds of the general structure (II*) can besynthesized by reacting an amine of the general structure (7) withactivated carboxylic acid derivatives of the general structure (8*). Inthis connection, the same conditions apply for the choice of solvent,the reaction conditions, the reaction time and the reagents as for thesynthesis of (II), described above.

Step 5

Compounds of the general structure (8) can be synthesized by reacting anamine of the general structure (10) with activated carboxylic acidderivatives of the general structure (9). In this connection, the sameconditions apply for the choice of solvent, the reaction conditions, thereaction time and the reagents as for the synthesis of (II), preferably(II′), more preferably (IIa), described in Step 6 above.

Compounds of Formula (III)

The present invention also refers to a process to produce aninsecticidal compound of formula (III) or (III′) based on thepreparation of compounds of formula (I).

in which

-   R¹ is (C₁-C₄)-alkyl, preferably methyl; and-   A₁ is C—R²;-   R² is hydrogen, fluorine, chlorine, bromine, CN, NO₂, optionally    halogenated C₁-C₆-alkyl, optionally halogenated C₁-C₄-alkoxy,    optionally halogenated C₁-C₄-alkylsulphonyl, optionally halogenated    C₁-C₄-alkylsulphinyl or N-cyclopropylaminocarbonyl    (—C(═O)—NH-cyclopropyl); preferably hydrogen, fluorine, chlorine,    bromine, CN, NO₂, methyl, ethyl, fluoromethyl, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy,    1-methylethoxy, fluoromethoxy, difluoromethoxy,    chlorodifluoromethoxy, dichlorofluoromethoxy, trifluoromethoxy,    2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy,    pentafluoroethoxy, methylsulphonyl, methylsulphinyl,    trifluoromethylsulphonyl, trifluoromethylsulphinyl or    N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine,    chlorine, bromine, CN, NO₂, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or    pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine,    most preferably chlorine; and-   A₂ is C—R³ or nitrogen;-   R³ is hydrogen, methyl, fluorine or chlorine, preferably hydrogen;    and-   Q is hydrogen, cyano, hydroxy, formyl or one of the groupings    C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₉-cycloalkyl,    C₃-C₉-heterocycloalkyl, C₁-C₄-alkoxy, C₄-C₁₅-alkylcycloalkyl,    C₄-C₁₅-cycloalkylalkyl, C₁-C₆-hydroxyalkyl, C₆-aryl-C₁-C₃-alkyl,    C₅-C₆-heteroaryl-C₁-C₃-alkyl, C₁-C₄-aminoalkyl,    aminocarbonyl-C₁-C₄-alkyl or C₁-C₄-alkyl-amino-C₁-C₄-alkyl which are    optionally substituted with one, two, three, four or five,    preferably with one or two, more preferably with one, substituents    independently selected from the group consisting of hydroxy, nitro,    amino, halogen, C₁-C₃-alkoxy, cyano, hydroxycarbonyl,    C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbamoyl,    C₄-C₆-cycloalkylcarbamoyl and optionally independently with one, two    or three substituents selected from the group consisting of halogen,    cyano, nitro, hydroxycarbonyl, C₁-C₂-alkylcarbamoyl, C₁-C₂-alkyl,    halogenated C₁-C₂-alkyl and C₁-C₂-alkoxy substituted phenyl;    preferably Q is C₃-C₆-cycloalkyl, or C₃-C₆-cycloalkyl which is    substituted with at least one substituent selected from the group    consisting of chlorine, fluorine, bromine, iodine, cyano and    hydroxy, or C₆-aryl-C₁-C₃-alkyl; more preferably cyclopropyl,    1-cyano-cyclopropyl or benzyl (—CH₂—C₆H₅);-   T represents one of the 5-membered heteroaromatics T1-T8 listed    below, where the bond to the pyrazole head group is marked with an    asterisk *,

wherein

-   R⁶ independently of one another represents halogen, cyano, nitro,    amino or optionally substituted C₁-C₆-alkyl, C₁-C₆-alkyloxy,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulphanyl, C₁-C₆-alkylsulphinyl,    C₁-C₆-alkylsulphonyl, and-   n represents the values 0-2, preferably 0, provided that n is 0 or 1    in T5, T6 and T8 and provided n is 0 in T7;    preferably, a compound of formula (III) is a compound of formula    (III′)

wherein A₁ and A₂ and T and Q have the meanings described above for acompound of formula (III) characterized in that the process comprisessteps 1 and 2 as described above.

For clarity sake, if n in any formula described herein is 0 (zero),carbon ring atoms with a free valence are then substituted by hydrogen.

In one preferred embodiment, the compound of formula (III) is compound(IIIa) defined by the following substituents:

R¹ T n R⁶ A¹ A² Q CH₃ T3 0 — C—Cl C—H 1-cyanocyclopropyl  

The new and inventive process for preparing a compound of formula (III),preferably (III′), more preferably (IIIa), is characterized in that theprocess steps 1 and 2 as described above. In a further preferredembodiment, the process comprises in addition to steps 1 and 2 asdescribed above the subsequent Step 7 and Step 8:

The radicals A₁, A₂, R¹ and Q have the meanings described for compound(III). Preferably, R¹ is methyl. The five-membered cycles of E₁-E₃,carbon and nitrogen represent the 5-membered heterocycles defined underT. U represents bromine, iodine or triflate if M represents a boronicacid, boronic ester or trifluoroboronate. U represents a boronic acid,boronic ester or trifluoroboronate if M represents bromine, iodine ortriflate.

Step 7

The compounds of the general structure (12) can be prepared by processesknown from the literature by, e.g., nucleophilic substitution of F atthe aromatic ring (WO2007-107470; Sakya et al., Tetrahedron Letters2003, 44, 7629-7632) from the appropriate starting materials of formula(I), preferably (Ia), more preferably (Ib), and (11).

Step 8

Compounds of formula (III) or (III′), preferably compound (IIIa), can beprepared by using palladium-catalysed reactions with the reactionpartners (12) and (13) (see, e.g., WO 2005/040110 or WO 2009/089508).The compounds of the general structure (13) are either commerciallyavailable or can be prepared by processes known to the person skilled inthe art.

Moreover, the skilled person is aware that it is alternatively possibleto react a compound of formula (12) with a compound of formula (13*),wherein the —C(═O)—NH-Q moiety of compounds of formula (13) is replacedby a C(═O)—OH or C(═O)-PG moiety in a compound of formula (13*), whereinPG stands for any protective group of a carboxylic group (e.g. analkylesther such as methylesther, i.e. PG represents —O-methyl). Thedeprotection of the carboxylic moiety of the resulting compound (III*)of a reaction with a compound (13*) and/or activating of the carboxylicmoiety and/coupling with an amine to arrive at a compound of formula(III) are well known to a skilled person.

In sum, compounds of the general structure (III) can be synthesized byreacting an amine of the general structure (10) with activatedcarboxylic acid derivatives of the general structure (III*). In thisconnection, the same conditions apply for the choice of solvent, thereaction conditions, the reaction time and the reagents as for thesynthesis of (II), described in Step 6 above.

Compounds of formula (III″)

In another preferred embodiment, the invention refers to a process toprepare a compound of formula (III″), preferably of formula (III′″),e.g., known from WO 2012/107434:

wherein R¹, R⁶, n, A₁, A₂, and Q are as defined for compound (III),preferably;preferably, a compound of formula (III″) is a compound of formula(III′″)

wherein R⁶, n, A₁, A₂ and Q are as defined for a compound of formula(III), preferably, wherein n is 0 characterized in that the processcomprises steps 1 and 2 as described above.

In one preferred embodiment, the compound of formula (III′″) is compound(IIIb) defined by the following substituents:

n R⁶ A¹ A² Q 0 — C—Cl C—H 1-cyanocyclopropyl

The process for preparing a compound of formula (III″), preferably(III′″), more preferably (IIIb), is characterized in that the processcomprises steps 1 and 2 as described above. In a further preferredembodiment, the process comprises in addition to steps 1 and 2 asdescribed above optionally Step 3 and Step 4 as described aboveoptionally the subsequent Step 7 and Step 8 as described above oroptionally the subsequent Step 9 and Step 10. Steps 11 and 12 are knownin the art (see, e.g., WO 2012/107434).

Step 9

In a Step 9, a compound of formula (I), preferably of formula (Ia), canbe transformed into its azido analogue of formula (14) or (14a),respectively:

wherein R¹ is hydrogen, optionally halogenated C₁-C₄-alkyl or optionallyhalogenated cyclopropyl, preferably methyl,preferably, a compound of formula (14) is compound (14a)

by reacting compound (I), preferably compound (Ia), more preferablycompound (Ib), with an azide-donor such an alkaline metal azide (e.g.,NaN₃).

Preferably, the reaction is carried out in a polar aprotic solvent suchas tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone,dimethylformamide (DMF), acetobitrile or dimethyl sulfoxide (DMSO). Onepreferred solvent is DMSO.

Typically, the reaction temperature is between 0° C. and 60° C.,preferably between 10° C. and 30° C., more preferably between 20° C. and30° C.

The reaction time can inter alia depend on the reaction volume and isusually between 0.5 h to 30 h.

Step 10

In a Step 10, an intermediate of formula (14), preferably of formula(14a), is reacted with an intermediate of formula (15) to give anintermediate of formula (III″*) or preferably a compound of formula(III′″*) wherein R¹ is methyl, respectively:

wherein R¹, R⁶, A₁, and A₂ are as defined for compound (III), n is 0 or1 and PG is any protective group of the carboxylic group such asC₁-C₆-alkyl (e.g., methyl). Preferably, R¹ in a compound of formula(III″*) is methyl (compound of formula (III′″*)). More preferably, R¹ informula (III″*) is methyl and n in formula (III″*) is 0.

Compounds of formula (15) are commercially available or can be preparedaccording to methods known in the art.

Typically, the solvent for reaction of Step 10 is a polar protic solventsuch as water, formic, n-butanol, isopropanol, nitromethane, ethanol,methanol, acetic acid or combinations thereof. Preferably, the solventis n-butanol, isopropanol, ethanol, water or combinations thereof.

The reaction is carried out in the presence of copper or a coppercatalyst such as copper sulfate or copper (I) iodide, optionally in thepresence of a base such as N-ethyldiisopropylamine. However, also otherorganic bases are suitable. In case of a Cu(II) catalyst, a reducingagent such as sodium ascorbate may be used. In case of Cu(0) catalyst,such as an amine salt, an oxidizing agent may be used (see, e.g.,Angewandte Chemie, International Edition (2009), 48(27), 4900-4908 andcited references, Lutz., Angew. Chem. Int. Ed. 2008, 47, 2182-2184 andcited references, and Bock et al., Eur. J. Org. Chem. (2006), 51-68 andcited references).

Starting from a compound of formula (III″*), compounds of formula (III),(III′), (III″), (III′″), (IIIb), (III″″), (IV) or (IV′) can be easilyprepared according to methods known in the art (see, e.g. WO2012/107434).

Step 11

Compound of formula (III″″) may be prepared by reaction of a compound offormula (III″*) wherein O-PG is C₁-C₆-alkoxy via hydrolysis. Forinstance, in the case wherein —O-PG is methoxy or ethoxy, the hydrolysiscan be done with water and a base, such as potassium hydroxide orlithium hydroxide, in the absence or in the presence of a solvent, suchas, for instance, tetrahydrofurane or methanol. In the case where R is,for example, tert-butoxy, the hydrolysis is done in the presence ofacid, such as trifluoroacetic acid or hydrochloric acid. The reaction iscarried out at a temperature of from −120° C. to 130° C., preferablyfrom −100° C. to 100° C.

wherein R¹, R⁶, n, A₁, and A₂ are as defined for compound (III),preferably R¹ is methyl and n is 0.

Compounds of the general structure (III) can be synthesized by reactingan amine of the general structure (10) with activated carboxylic acidderivatives of the general structure (III″″). In this connection, thesame conditions apply for the choice of solvent, the reactionconditions, the reaction time and the reagents as for the synthesis of(II) described in Step 6 above.

Compounds of Formula (IV)

One aspect of the present invention refers to a process for thepreparation of a compound of formula (IV), preferably of formula (IV′):

in which

-   R¹ is C₁-C₄-alkyl, preferably methyl; and-   A₁ is C—R²; and-   R² is hydrogen, fluorine, chlorine, bromine, CN, NO₂, optionally    halogenated C₁-C₆-alkyl, optionally halogenated C₁-C₄-alkoxy,    optionally halogenated C₁-C₄-alkylsulphonyl, optionally halogenated    C₁-C₄-alkylsulphinyl or N-cyclopropylaminocarbonyl    (—C(═O)—NH-cyclopropyl); preferably hydrogen, fluorine, chlorine,    bromine, CN, NO₂, methyl, ethyl, fluoromethyl, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy,    1-methylethoxy, fluoromethoxy, difluoromethoxy,    chlorodifluoromethoxy, dichlorofluoromethoxy, trifluoromethoxy,    2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy,    pentafluoroethoxy, methylsulphonyl, methylsulphinyl,    trifluoromethylsulphonyl, trifluoromethylsulphinyl or    N-cyclopropylaminocarbonyl, more preferably hydrogen, fluorine,    chlorine, bromine, CN, NO₂, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or    pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine,    most preferably chlorine; and-   A₂ is C—R³ or nitrogen; and-   R³ is hydrogen, methyl, fluorine or chlorine, preferably hydrogen;    and-   T represents one of the 5-membered heteroaromatics T1-T9 listed    below, where the bond to the pyrazole head group is marked with an    asterisk *,

-   R⁶ independently of one another represents halogen, cyano, nitro,    amino or optionally substituted C₁-C₆-alkyl, C₁-C₆-alkyloxy,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulphanyl, C₁-C₆-alkylsulphinyl,    C₁-C₆-alkylsulphonyl, and-   n represents the values 0-2, preferably 0, provided that n is 0 or 1    in T5, T6 and T8 and provided n is 0 in T7.-   Q is hydrogen, cyano, hydroxy, formyl or one of the groupings    C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₉-cycloalkyl,    C₃-C₉-heterocycloalkyl, C₁-C₄-alkoxy, C₄-C₁₅-alkylcycloalkyl,    C₄-C₁₅-cycloalkylalkyl, C₁-C₆-hydroxyalkyl, C₆-aryl-C₁-C₃-alkyl,    C₅-C₆-heteroaryl-C₁-C₃-alkyl, C₁-C₄-aminoalkyl,    aminocarbonyl-C₁-C₄-alkyl or C₁-C₄-alkyl-amino-C₁-C₄-alkyl which are    optionally substituted with one, two, three, four or five,    preferably with one or two, more preferably with one, substituents    independently selected from the group consisting of hydroxy, nitro,    amino, halogen, C₁-C₃-alkoxy, cyano, hydroxycarbonyl,    C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbamoyl,    C₄-C₆-cycloalkylcarbamoyl and optionally independently with one, two    or three substituents selected from the group consisting of halogen,    cyano, nitro, hydroxycarbonyl, C₁-C₂-alkylcarbamoyl, C₁-C₂-alkyl,    halogenated C₁-C₂-alkyl and C₁-C₂-alkoxy substituted phenyl;    preferably Q is C₃-C₆-cycloalkyl, or C₃-C₆-cycloalkyl which is    substituted with at least one substituent selected from the group    consisting of chlorine, fluorine, bromine, iodine, cyano and    hydroxy, or C₆-aryl-C₁-C₃-alkyl; more preferably cyclopropyl,    1-cyano-cyclopropyl or benzyl (—CH₂—C₆H₅);    preferably, a compound of formula (IV) is a compound of formula    (IV′):

wherein T, A₁, A₂ and Q are as defined for a compound of formula (IV),preferably wherein T is selected from T3, T8 or T9 wherein the processis characterized in that the process comprises steps 1 and 2 asdescribed above.

One preferred embodiment refers to a process for the preparation ofcompound (IV) where R¹—in all formulae disclosed herein wherein R¹ ispresent—represents methyl.

Another preferred embodiment refers to a process for the preparation ofcompound (IV) where n—in all formulae disclosed herein wherein n ispresent—represents 0.

Another preferred embodiment refers to a process for the preparation ofcompound (IV) where A₁—in all formulae disclosed herein wherein A₁ ispresent—represents C—R², wherein R² represents hydrogen, fluorine,chlorine or bromine, most preferably wherein R² represents chlorine.

Another preferred embodiment refers to a process for the preparation ofcompound (IV) where A₂—in all formulae disclosed herein wherein A₂ ispresent—represents C—R³ wherein R³ represents hydrogen.

Another preferred embodiment refers to a process for the preparation ofcompound (IV) where T—in formula (IV) and all further formulae disclosedherein wherein T is present—represents T3, T8 or T9.

Another preferred embodiment refers to a process for the preparation ofcompound IV where Q—in all formulae disclosed herein wherein Q ispresent— represents optionally with cyano substituted C₃-C₆-cycloalkylor C₆-aryl-C₁-C₃-alkyl even more preferred Q represents optionally withcyano substituted C₃-cycloalkyl or benzyl, even more preferred, Qrepresents with cyano substituted cyclopropyl (e.g., 1-cyanocyclopropyl)or benzyl.

Another preferred embodiment refers to a process for the preparation ofcompound (IV) where R¹—in all formulae disclosed herein wherein R¹ ispresent—represents methyl and n—in all formulae disclosed herein whereinn is present—represents 0 and A₁—in all formulae disclosed hereinwherein A₁ is present—represents C—Cl and A₂—in all formulae disclosedherein wherein A₂ is present—represents C—H and where T—in formula (IV)and all further formulae disclosed herein wherein T ispresent—represents T3, T8 or T9, and Q in all formulae disclosed hereinwherein Q is present represents optionally with cyano substitutedC₃-C₆-cycloalkyl or C₆-aryl-C₁-C₃-alkyl.

Another preferred embodiment refers to a process for the preparation ofcompound IV where R¹—in all formulae disclosed herein wherein R¹ ispresent—represents methyl and T—in all formulae disclosed herein whereinT is present—represents T3, T8 or T9 and n—in all formulae disclosedherein wherein n is present—represents 0 and A₁—in all formulaedisclosed herein wherein A₁ is present—represents C—Cl and A₂—in allformulae disclosed herein wherein A₂ is present—represents C—H and Q—inall formulae disclosed herein wherein Q is present—represents with cyanosubstituted cyclopropyl (e.g. 1-cyano-cyclopropyl) or benzyl.

The present invention also refers to a process for the preparation of acompound of formula (6), preferably of formula (6a), comprising thesteps 1 and 2 as described above optionally Step 3 and Step 4 asdescribed above.

The present invention also refers to a process for the preparation of acompound of formula (6), preferably of formula (6a), comprising thesteps 1 and 2 as described above optionally Step 3 and Step 4 asdescribed above. Or comprising the steps 1 and 2 as described above andStep 3 as described above.

The present invention also refers to a process for the preparation of acompound of formula (7), preferably of formula (7a), comprising thesteps 1 and 2 as described above.

The present invention also refers to a process for the preparation of acompound of formula (7), preferably of formula (7a), comprising thesteps 1 and 2 as described above; or to a process for the preparation ofa compound of formula (I), preferably of formula (7a) comprising thesteps 1 and 2 as described above and Step 3 and Step 4 as describedabove.

In one aspect, the present invention also refers to the use of compoundsof formula (I) prepared by a process comprising at least steps 1 and 2as described above to prepare a compound of formula (II), preferably offormula (IIa).

Moreover, the present invention also refers to the use of compounds offormula (1) prepared by a process comprising at least steps 1 and 2 asdescribed above to prepare a compound of formula (III), preferably offormula (III′), more preferably of formula (IIIa).

Moreover, the present invention also refers to the use of compounds offormula (1) prepared by a process comprising at least steps 1 and 2 asdescribed above to prepare a compound of formula (III″), preferably offormula (III′″), more preferably of formula (IIIb).

Moreover, the present invention also refers to the use of compounds offormula (1) prepared by a process comprising at least steps 1 and 2 asdescribed above to prepare a compound of formula (IV), preferably offormula (IV′).

SUMMARY

An aspect of the present invention refers to a process for the synthesisof 5-fluoro-1H-pyrazoles of the general formula (I)

-   -   by reacting an olefin of the general formula (a)

-   -   with nucleophiles, and optionally a base,    -   followed by reaction with hydrazines of formula (b)        R¹—NH—NH₂  (b),    -   wherein    -   R¹ is selected from C₁-C₆ alkyl, cycloalkyl, C₅-C₁₀ aryl;    -   R² is a trihalomethyl moiety with at least one fluorine atom;        and    -   R³ is selected from C₁-C₅ haloalkyl as CF₃, CF₂C, C₂F₅, C₃F₇,        CF₂CF₂Cl, CFClCF₃.    -   and the nucleophile is not water.

A preferred embodiment refers to a process described above, wherein thenucleophile is selected from alcohols, thioles or secondary amines, andin case the nucleophile is an alcohol or a thiol, also in the presenceof a base.

A preferred embodiment refers to a process described above, wherein

-   -   R¹ is methyl    -   R² is CF₃    -   R³ is C₂F₅,

A preferred embodiment refers to a process described above, wherein thenucleophile is methanol and the base is triethylamine.

Another aspect refers to a process for the preparation of a compound offormula (IV)

-   -   in which    -   R¹ is C₁-C₄-alkyl; and    -   A₁ is C—R²; and    -   R² is hydrogen, fluorine, chlorine, bromine, CN, NO₂, optionally        halogenated C₁-C₆-alkyl, optionally halogenated C₁-C₄-alkoxy,        optionally halogenated C₁-C₄-alkylsulphonyl, optionally        halogenated C₁-C₄-alkylsulphinyl or N-cyclopropylaminocarbonyl        (—C(═O)—NH—cyclopropyl); preferably hydrogen, fluorine,        chlorine, bromine, CN, NO₂, methyl, ethyl, fluoromethyl,        difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy,        ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy,        difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy,        trifluoromethoxy, 2,2,2-trifluoroethoxy,        2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulphonyl,        methylsulphinyl, trifluoromethylsulphonyl,        trifluoromethylsulphinyl or N-cyclopropylaminocarbonyl, more        preferably hydrogen, fluorine, chlorine, bromine, CN, NO₂,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl,        2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy,        preferably hydrogen, fluorine, chlorine, bromine, most        preferably chlorine; and    -   A₂ is C—R³ or nitrogen; and    -   R³ is hydrogen, methyl, fluorine or chlorine, preferably        hydrogen; and    -   T represents one of the groups T1-T9 listed below, where the        bond to the pyrazole head group is marked with an asterisk *,

-   -   R⁶ independently of one another represents halogen, cyano,        nitro, amino or optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkyloxy, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulphanyl,        C₁-C₆-alkylsulphinyl, C₁-C₆-alkylsulphonyl, and    -   n represents the values 0-2, preferably 0, provided that n is 0        or 1 in T5, T6 and T8 and provided    -   n is 0 in T7; and    -   Q is hydrogen, cyano, hydroxy, formyl or one of the groupings        C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₉-cycloalkyl,        C₃-C₉-heterocycloalkyl, C₁-C₄-alkoxy, C₄-C₁₅-alkylcycloalkyl,        C₄-C₁₅-cycloalkylalkyl, C₁-C₆-hydroxyalkyl, C₆-aryl-C₁-C₃-alkyl,        C₅-C₆-heteroaryl-C₁-C₃-alkyl, C₁-C₄-aminoalkyl,        aminocarbonyl-C₁-C₄-alkyl or C₁-C₄-alkyl-amino-C₁-C₄-alkyl which        are optionally substituted with one, two, three, four or five,        preferably with one or two, more preferably with one,        substituents independently selected from the group consisting of        hydroxy, nitro, amino, halogen, C₁-C₃-alkoxy, cyano,        hydroxycarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbamoyl,        C₄-C₆-cycloalkylcarbamoyl and optionally independently with one,        two or three substituents selected from the group consisting of        halogen, cyano, nitro, hydroxycarbonyl, C₁-C₂-alkylcarbamoyl,        C₁-C₂-alkyl, halogenated C₁-C₂-alkyl and C₁-C₂-alkoxy        substituted phenyl; preferably Q is C₃-C₆-cycloalkyl, or        C₃-C₆-cycloalkyl which is substituted with at least one        substituent selected from the group consisting of chlorine,        fluorine, bromine, iodine, cyano and hydroxy, or        C₆-aryl-C₁-C₃-alkyl; more preferably cyclopropyl,        1-cyano-cyclopropyl or benzyl (—CH₂—C₆H₅);    -   comprising the steps according to any one of claim 1 to claim 4.

A preferred embodiment refers to a process described above, wherein acompound of formula (IV) is a compound of formula (II), preferably offormula (II′).

A preferred embodiment refers to a process described above, wherein acompound of formula (IV) is compound (IIa).

A preferred embodiment refers to a process described above, furthercomprising the steps of:

-   -   reacting compound (I) with a cyano-donor to prepare intermediate        of formula (6)

-   -   wherein R¹ is (C₁-C₄)-alkyl; and    -   reacting compound (6) with an inorganic strong base in a first        hydrolysis step followed by adding an inorganic acid in a second        hydrolysis step to prepare intermediate of formula (7)

wherein

R¹ is (C₁-C₄)-alkyl; and

-   -   reacting a compound of formula (8) or its salt (8′) with an        activated form (7′) of compound (7)

-   -   wherein R¹, A₁, A₂, and Q are as defined in claim 5 and LG is        any leaving group,

to prepare a compound of formula (II).

A preferred embodiment refers to a process described above, wherein acompound of formula (IV) is a compound of formula (III)

-   -   in which    -   R¹ is (C₁-C₄)-alkyl; and    -   A₁ is C—R²;    -   R² is hydrogen, fluorine, chlorine, bromine, CN, NO₂, optionally        halogenated C₁-C₆-alkyl, optionally halogenated C₁-C₄-alkoxy,        optionally halogenated C₁-C₄-alkylsulphonyl, optionally        halogenated C₁-C₄-alkylsulphinyl or N-cyclopropylaminocarbonyl        (—C(═O)—NH-cyclopropyl); preferably hydrogen, fluorine,        chlorine, bromine, CN, NO₂, methyl, ethyl, fluoromethyl,        difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy,        ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy,        difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy,        trifluoromethoxy, 2,2,2-trifluoroethoxy,        2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulphonyl,        methylsulphinyl, trifluoromethylsulphonyl,        trifluoromethylsulphinyl or N-cyclopropylaminocarbonyl, more        preferably hydrogen, fluorine, chlorine, bromine, CN, NO₂,        methyl, fluoromethyl, difluoromethyl, trifluoromethyl,        2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy,        preferably hydrogen, fluorine, chlorine, bromine, most        preferably chlorine; and    -   A₂ is C—R³ or nitrogen;    -   R³ is hydrogen, methyl, fluorine or chlorine, preferably        hydrogen; and    -   Q is hydrogen, cyano, hydroxy, formyl or one of the groupings        C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₉-cycloalkyl,        C₃-C₉-heterocycloalkyl, C₁-C₄-alkoxy, C₄-C₁₅-alkylcycloalkyl,        C₄-C₁₅-cycloalkylalkyl, C₁-C₆-hydroxyalkyl, C₆-aryl-C₁-C₃-alkyl,        C₅-C₆-heteroaryl-C₁-C₃-alkyl, C₁-C₄-aminoalkyl,        aminocarbonyl-C₁-C₄-alkyl or C₁-C₄-alkyl-amino-C₁-C₄-alkyl which        are optionally substituted with one, two, three, four or five,        preferably with one or two, more preferably with one,        substituents independently selected from the group consisting of        hydroxy, nitro, amino, halogen, C₁-C₃-alkoxy, cyano,        hydroxycarbonyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylcarbamoyl,        C₄-C₆-cycloalkylcarbamoyl and optionally independently with one,        two or three substituents selected from the group consisting of        halogen, cyano, nitro, hydroxycarbonyl, C₁-C₂-alkylcarbamoyl,        C₁-C₂-alkyl, halogenated C₁-C₂-alkyl and C₁-C₂-alkoxy        substituted phenyl; preferably Q is C₃-C₆-cycloalkyl, or        C₃-C₆-cycloalkyl which is substituted with at least one        substituent selected from the group consisting of chlorine,        fluorine, bromine, iodine, cyano and hydroxy, or        C₆-aryl-C₁-C₃-alkyl; more preferably cyclopropyl,        1-cyano-cyclopropyl or benzyl (—CH₂—C₆H₅);    -   T represents one of the 5-membered heteroaromatics T1-T8 listed        below, where the bond to the pyrazole head group is marked with        an asterisk *,

-   -   wherein    -   R⁶ independently of one another represents halogen, cyano,        nitro, amino or optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkyloxy, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulphanyl,        C₁-C₆-alkylsulphinyl, C₁-C₆-alkylsulphonyl, and    -   n represents the values 0-2, preferably 0, provided that n is 0        or 1 in T5, T6 and T8 and provided n is 0 in T7.

A preferred embodiment refers to a process described above, wherein acompound of formula (III) is compound of formula (III′), more preferablycompound (IIIa) or compound (IIIb).

A preferred embodiment refers to a process described above, furthercomprising the steps of

-   -   reacting a compound of formula (I) with an intermediate of        formula (11) by nucleophilic substitution of the fluoride at the        ring position of a compound of formula (I) (herein referred to        as Step 9)

-   -   wherein    -   R¹ is optionally halogenated (C₁-C₄)-alkyl or optionally        halogenated cyclopropyl; and    -   U represents bromine, iodine, triflate, boronic acid, boronic        ester or trifluoroboronate; and    -   the five-membered cycles of E₁-E₃, carbon and nitrogen represent        the 5-membered heterocycles selected from the group consisting        of

-   -   wherein    -   R⁶ independently of one another represents halogen, cyano,        nitro, amino or optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkyloxy, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulphanyl,        C₁-C₆-alkylsulphinyl, C₁-C₆-alkylsulphonyl, and    -   n represents the values 0-2, preferably 0, provided that n is 0        or 1 in T5, T6 and T8 and provided n is 0 in T7;    -   to prepare an intermediate of formula (12); and    -   reacting a compound of formula (12) and a compound of        formula (13) (herein referred to as Step 10)

-   -   wherein R¹, A₁, A₂, and Q are as defined for a compound of        formula (III) and U represents bromine, iodine, triflate,        boronic acid, boronic ester or trifluoroboronate; and the        five-membered cycles of E₁-E₃, carbon and nitrogen represent the        5-membered heterocycles selected from the group consisting of

-   -   wherein    -   R⁶ independently of one another represents halogen, cyano,        nitro, amino or optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkyloxy, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulphanyl,        C₁-C₆-alkylsulphinyl, C₁-C₆-alkylsulphonyl, and    -   n represents the values 0-2, preferably 0, provided that n is 0        or 1 in T5, T6 and T8 and provided n is 0 in T7; and    -   M represents bromine, iodine or triflate when U represents a        boronic acid, boronic ester or trifluoroboronate; or    -   M represents a boronic acid, boronic ester or trifluoroboronate        when U represents bromine, iodine or triflate    -   to prepare a compound of formula (III).

A preferred embodiment refers to a process described above, wherein acompound of formula (IV) is a compound of formula (III″), preferably offormula (III′″).

A preferred embodiment refers to a process described above

a) further comprising the steps as described in claim 11; or

b) further comprising the steps of

-   -   reacting a compound of formula (I) and an azide-donoer to        prepare intermediate (14)

-   -   wherein R¹ is as defined for a compound of formula (III); and    -   reacting intermediate (14) with an intermediate of formula (15)        to give an intermediate (III″*) (herein referred to as Step 12)

-   -   wherein R¹, R⁶, A₁, and A₂ are as defined for compound (III), n        is 0 or 1 and PG is any protective group of the carboxylic group        such as C₁-C₆-alkyl (e.g., methyl).

Process described above, wherein R¹ is methyl.

Example 1N-Methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole

In a 2 l 3-k neck flask equipped with condenser, thermometer, and adropping funnel 1300 ml methylene chloride andperfluoro-2-methyl-2-pentene (197 g, 0.65 mol) was placed, and then 25 gMethanol were added. The mixture was cooled to −0° C. and Et₃N (164 g,1.62 mol) was added at a temperature ranging from −5° to 5° C. Themixture was stirred at this temperature for 15 min and a solution of 100ml N-methylhydrazine in water (40% w.w.) was slowly added to thismixture at 5° C. within 2 h. The reaction mixture was stirred for 15-20h at 20° C. The mixture was washed with water, the organic layer wasdried over Na₂SO₄ and the solvent was distilled off under atmosphericpressure. The crude product was purified via vacuum distillation. Theyield ofN-Methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole was140 g (80% yield). Boiling point 62-67° C. at 15-20 mbar.

¹⁹F NMR δ: 53.7 (3F), 83.9 (3F), 112.1 (2F), 125.1 (1F) ppm.

Example 2N-Methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole

In a 2 l 3-k neck flask equipped with condenser, thermometer, and adropping funnel 1300 ml methylene chloride andperfluoro-2-methyl-2-pentene (197 g, 0.65 mol) was placed, and then 46 gEthanol were added. The mixture was cooled to −0° C. and Et₃N (164 g,1.62 mol) was added at a temperature ranging from −5° to 5° C. Themixture was stirred at this temperature for 15 min and a solution of 100ml N-methylhydrazine in water (40% w.w.) was slowly added to thismixture at 5° C. within 2 h. The reaction mixture was stirred for 15-20h at 20° C. The mixture was washed with water, the organic layer wasdried over Na₂SO₄ and the solvent was distilled off under atmosphericpressure. The crude product was purified via vacuum distillation. Theyield ofN-Methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole was139 g (75% yield). Boiling point 62-67° C. at 15-20 mbar.

Example 3N-Methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-H-pyrazole

In a 2 l 3-k neck flask equipped with condenser, thermometer, and adropping funnel 1300 ml methylene chloride andperfluoro-2-methyl-2-pentene (197 g, 0.65 mol) was placed, and then 48 gDiethylamin were added. The mixture was cooled to −0° C. and Et₃N (164g, 1.62 mol) was added at a temperature ranging from −5° to 5° C. Themixture was stirred at this temperature for 15 min and a solution of 100ml N-methylhydrazine in water (40% w.w.) was slowly added to thismixture at 5° C. within 2 h. The reaction mixture was stirred for 15-20h at 20° C. The mixture was washed with water, the organic layer wasdried over Na₂SO₄ and the solvent was distilled off under atmosphericpressure. The crude product was purified via vacuum distillation. Theyield ofN-Methyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole was145 g (78% yield). Boiling point 62-67° C. at 15-20 mbar.

Example 4N-Ethyl-3-pentafluoroethyl-4-trifluoromethyl-5-fluoro-1H-pyrazole

obtained from perfluoro-2-methyl-2-pentene and N-Ethylhydrazinenaccording to the example 2.

Yield 83%, boiling point 70° C. at 18-20 mbar.

Example 5 (Step 3) Preparation of5-Cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole(intermediate (6a))

28.6 g (0.1 mol) of5-fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole (compound(la)) and 9.7 g (0.15 mol) of potassium cyanide are suspended in 150 mlof acetonitrile and then heated under reflux for 5h under a protectivegas atmosphere. After cooling, the precipitate (KCN, KF) was filteredoff, and the solvent was removed in vacuo 300 mbar to give a brawn oil(27.8 g, 95%) which was used for further step without any purification.

¹H-NMR (400 MHz, d₃-acetonitrile): δ=4.11 (s, 3H, CH₃) ppm

¹⁹F-NMR (400 MHz, CDCl₃): δ=−56.7 (3F), −111.4 (3F), −111.6 (2F) ppm.

GC-MS: Retention time 2.67 min; mass (m/z): 224 (M)⁺.

Example 6 (Step 4) Preparation of1-Methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole-5-carboxylicacid (intermediate (7a))

29.3 g (0.1 M) of5-cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole (compound(6a)) and 110 g of 10% NaOH were heated in an oil bath at 100° C. for 6h until clear solution formed. After cooling to 5° C., the reactionmixture was slowly acidify to pH 1 by adding of 37% HCl to give a whitecrystals which were filtered off, washed with 40 ml cold water and driedyielding 28 g (7a) of1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole-5-carboxylic acid)as a white solid with m.p. 120-122° C.

¹H-NMR (400 MHz, d₃-acetonitrile) δ=4.08 (s, 3H, CH₃) ppm;

HPLC-MS^(a)): log P=1.86; mass (m/z): 313.0 (M+H)⁺.

Example 7 (Step 7) Preparation of4-bromo-2′-methyl-5′-(pentafluoroethyl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole(intermediate (12))

2.00 g (6.99 mmol) of5-fluoro-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole(compound (Ia)), 1.03 g (6.99 mmol) of 4-bromo-1H-pyrazole (compound offormula (11)) and 1.93 g of potassium carbonate are suspended in 50 mlof tetrahydrofuran p.a. The reaction mixture is heated under reflux for16 h. The cooled reaction mixture is filtered and the solvent is removedunder reduced pressure. The residue is purified by column chromatographyon silica gel.

This gives 0.69 g of4-bromo-2′-methyl-5′-(pentafluoroethyl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazoleas a colourless solid.

¹H-NMR (400 MHz, d₃-acetonitrile): δ=8.00 (s, 1H), 7.91 (s, 1H), 3.71(s, 3H).

HPLC-MS^(a)): log P=4.14, mass (m/z)=413 [M+H]⁺.

Example 8 (Step 8) Preparation of2-Chloro-N-1-cyan-cyclopropyl-5-[2′-methy-5′-(pentafluoroethy)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazol-4-yl]benzamide(compound (IIIa))

150 mg (0.36 mmol)4-bromo-2′-methyl-5′-(pentafluoroethyl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole,126 mg (0.36 mmol)2-chloro-N-(1-cyanocyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzamide,21 mg (0.01 mmol) tetrakis(triphenylphosphin)palladium and 1.1 ml of 1Maqueous sodium bicarbonate were mixed with 10.5 ml isopropanol andheated under reflux for 3h. The solvent is removed under reducedpressure and the residue is dissolved in ethylacetat. The organic phasewas washed two times with water, dried over Na₂SO₄, and filtered. Thesolvent is removed under reduced pressure. The residue was purified viecolumn chromatography with silica gel, yielding 98 mg2-chloro-N-(1-cyanocyclopropyl)-5-[2′-methyl-5′-(pentafluoroethyl)-4′-(trifuoromethyl)-2′H-1,3′-bipyrazole-4-yl]benzamideas colorless solid.

¹H-NMR (400 MHz, d₃-Acetonitril): δ=¹H-NMR (400 MHz, d3-Acetonitril):δ=8.27 (s, 1H), 8.25 (s, 1H), 7.75 (d, 1H), 7.70 (dd, 1H), 7.62 (s, 1H),7.51 (d, 1H), 3.75 (s, 3H), 1.56-1.60 (m, 2H), 1.33-1.36 (m, 2H).

HPLC-MS^(a)): log P=3.72, Masse (m/z)=553.1 [M+H]⁺.

Example 9 (Step 9) Preparation of5-Azido-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole(intermediate (14), R¹=methyl)

5-Fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole(prepared according to steps 1 to 4; 7 mmol) is added to a mixture ofdimethyl sulfoxide (DMSO) (10 ml). Sodium azide (0.5 g; 7.7 mmol) isthen added into the mixture, which is kept at room temperature. Themixture is stirred overnight at RT.

After the reaction is complete, a mixture of water (100 mL) and diethylether (100 mL) is added. The phases are separated and the aqueous phaseextracted twice with diethyl ether. This compound is used without extrapurification.

Example 10 (Step 10) Preparation of2-Chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoicacid methyl ester (see intermediate (III″*))

2-Chloro-5-ethynyl-benzoic acid methyl ester (1.13 g, 5.8 mmol) and5-Azido-1-methyl-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (1.80g, 5.8 mmol) is suspended in a mixture of water and t-BuOH (30 ml).Sodium ascorbate (0.600 ml 1 M sol. in water, freshly prepared) is addedto the mixture followed by copper (II) sulfate pentahydrate (0.015 g).The resulting heterogeneous mixture is stirred vigorously for 96 hours.The reaction mixture is diluted with water and the product extractedwith ethyl acetate. The organic phase is washed with brine, dried overmagnesium sulphate and evaporated. The residue is subjected to silicagel column chromatography (c-HEX/EtOAc=3:1) affording the desiredproduct2-Chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-H-[1,2,3]triazol-4-yl]-benzoicacid methyl ester (yield 53%).

¹H-NMR (400 MHz, CDCl₃): δ=8.47 (s, 1H), 8.12 (s, 1H), 8.0 (d, 1H), 7.62(d, 1H), 3.98 (s, 3H), 3.87 (s, 3H) ppm.

LC-MS RT 2.12, 504 (M+H+), 545 (M+CH₃CN+H⁺)

Example 11 (Step 11) Preparation of2-Chloro-5-[l-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoicacid (see compound of formula (III″″))

2-Chloro-5-[1-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoicacid methyl ester (1.53 g, 3.0 mmol) is suspended in a mixture of waterand tetrahydrofuran (1:3, 50 mL) and lithium hydroxide (0.22 g, 9.1mmol) is added. The resulting mixture is stirred vigorously for 5 hoursat 60° C. The reaction mixture is diluted with water and acidified withhydrogen chloride (2N). The aqueous phase is extracted twice with AcOEt,dried over MgSO₄ and concentrated under vacuum to afford the desiredproduct2-Chloro-5-[l-(2-methyl-5-pentafluoroethyl-4-trifluoromethyl-2H-pyrazol-3-yl)-1H-[1,2,3]triazol-4-yl]-benzoicacid. This compound was used without extra purification.

¹H-NMR (400 MHz, CDCl₃): δ=8.52 (s, 1H), 8.18 (s, 1H), 8.09 (d, 1H),7.66 (d, 1H), 3.88 (s, 3H) ppm.

LC-MS RT 2.08, 488 (M+H⁺).

Example 12 (Step 6) Preparation ofN-[4-chloro-3-(benzylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide(compound (IIa))

560 mg (1.79 mmol) of1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole-5-carboxylic acidwere suspended in 10 ml of dichloromethane. The suspension was cooled to0° C. and then subsequently admixed with 0.02 ml ofN,N-dimethylformamide and 188 μl (2.15 mmol; 1.2 eq) oxalyl chloride.The reaction mixture was stirred firstly for 0.5 h at 0° C. and then for3 hours at room temperature. The solvent was removed under reducedpressure on a rotary evaporator. The resultingI-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonylchloride was used for the subsequent synthesis step without furtherwork-up.

88.7 mg (0.34 mmol) of 5-amino-N-benzyl-2-chlorobenzamide, 2.77 mg (0.02mmol) of N,N-dimethylpyridine-4-amine (DMPA) are dissolved in 2.5 ml ofethyl acetate. The solution is cooled to 0° C. using an ice bath andadmixed with 119 μl (0.68 mmol) of N-ethyldiisopropylamine. 75.0 mg(0.22 mmol) of1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonylchloride are suspended in 2.5 ml of ethyl acetate and then added to thecooled reaction solution. The reaction mixture is heated for four hoursat 50° C. and then stirred for 16 hours at room temperature. Thereaction solution is diluted with 10.0 ml of ethyl acetate. The organicphase is washed three times with 1M hydrochloric acid, twice with 1Msodium hydroxide solution and once with saturated sodium chloridesolution. The organic phase is dried over sodium sulphate and filteredand solvent is removed under reduced pressure on a rotary evaporator.This gives 140 mg (0.17 mmol) ofN-[4-chloro-3-(benzylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide(97%) as white solid.

¹H-NMR (400 MHz, d₃-acetonitrile): δ=9.29 (bs, 1H), 7.78 (d, 1H), 7.67(dd, 1H), 7.48 (d, 1H), 7.21-7.52 (m, 6H), 4.54 (d, 2H), 3.97 (s, 3H)ppm.

HPLC-MS^(a)): log P=3.90 mass (m/z)=555.1 [M+H]⁺. ¹ The stated mass isthe peak of the isotope pattern of the [M+H]⁺ ion with the highestintensity.^(a)) Note regarding the determination of the log P values andmass detection: The log P values given were determined in accordancewith EEC Directive 79/831 Annex V.A8 by HPLC (High Performance LiquidChromatography) on a phase inversion column (C18). Agilent 1100 LCsystem; 50*4.6 Zorbax Eclipse Plus C18 1.8 micron; eluent A:acetonitrile (0.1% formic acid); eluent B: water (0.09% formic acid);linear gradient from 10% acetonitrile to 95% acetonitrile in 4.25 min,then 95% acetonitrile for a further 1.25 min; oven temperature 55° C.;flow: 2.0 ml/min. The mass detection is carried out via an Agilend MSDsystem.

The invention claimed is:
 1. A process for the synthesis of a 5-fluoro-1H-pyrazoles of formula (I)

by reacting an olefin of formula (a)

with one or more nucleophiles, and optionally a base, followed by reacting with one or more hydrazines of formula (b) R¹—NH—NH₂  (b), wherein R¹ is selected from C₁-C₆ alkyl, cycloalkyl, or C₅-C₁₀ aryl; R² is a trihalomethyl moiety with at least one fluorine atom; and R³ is selected from C₁-C₅ haloalkyl; and the nucleophile is not water.
 2. Process according to claim 1, wherein the nucleophile is selected from alcohols, thioles or secondary amines, and in case the nucleophile is an alcohol or a thiol, is also in the presence of a base.
 3. Process according to claim 1, wherein R¹ is methyl, R² is CF₃, and R³ is C₂F₅.
 4. Process according to claim 1, wherein the nucleophile is methanol and the base is used and is triethylamine.
 5. Process according to claim 1, wherein R¹ is methyl.
 6. Process according to claim 1, wherein the nucleophile is a thiol.
 7. Process according to claim 1, wherein the nucleophile is a secondary amine.
 8. Process according to claim 1, wherein the nucleophile is an alcohol.
 9. Process according to claim 1, wherein the nucleophile is an alcohol and is used in the presence of the base.
 10. Process according to claim 1, wherein the nucleophile is a thiol and is used in the presence of the base.
 11. Process according to claim 1, wherein R³ is selected from CF₃, CF₂Cl, C₂F₅, C₃F₇, CF₂CF₂Cl, or CFClCF₃.
 12. Process according to claim 1, wherein R¹ is selected from C₁-C₆ alkyl.
 13. Process according to claim 1, wherein the nucleophile is one or more of methanol, ethanol, isopropanol, benzylalcohol, methylamine, ethylamine or dimethylamine.
 14. Process according to claim 3, wherein the nucleophile is one or more of methanol, ethanol, isopropanol, benzylalcohol, methylamine, ethylamine or dimethylamine.
 15. Process according to claim 3, wherein the nucleophile is methanol and the base is used and is trimethylamine. 